Aztreonam-avibactam cracks into hard-to-treat MBL-producing MDR-GNB

The fixed-dose combination of aztreonam and avibactam yields a 41.7-percent clinical cure rate in serious infections caused by metallo-β-lactamase (MBL)–producing multidrug-resistant (MDR) Gram-negative bacteria (GNB), according to the results from the phase III ASSEMBLE trial.

MBLs are Amber class B β-lactamases that hydrolyze virtually all clinically available β-lactam antibiotics, including carbapenems, and therefore represent “a significant threat to patients and healthcare systems as treatment options are extremely limited,” said Professor George Daikos from the National and Kapodistrian University of Athens in Athens, Greece, on behalf of the investigators in ASSEMBLE at ESCMID Global 2024. [Lancet Infect Dis 2010;10:597-602; ESCMID 2024, poster E0846]

For patients with serious infections due to MBL-producing GNB, the outcomes are typically dismal, and can be illustrated by the 0-percent clinical cure rate observed with best available therapy (BAT) in the trial.

Outsmarting resistance mechanisms

For over 30 years, the only clinically available β-lactam antibiotic that is not degraded by MBLs is aztreonam, as the monobactam lacks the usual secondary ring adjacent to the β-lactam ring. [J Antimicrob Chemother 2016;71:2704-2712] However, MBL-producing GNB generally co-express other resistance mechanisms, such as serine β-lactamases, which render aztreonam ineffective.

Therefore, the combination of avibactam, a non–β-lactam β-lactamase inhibitor that effectively inhibits serine β-lactamases, with aztreonam can restore the activity of the monobactam against MBL-producing GNB. [Antimicrob Agents Chemother 2019;63:e00010-19] This novelty was tested in the pathogen-focused randomized ASSEMBLE trial, specifically addressing MBL-producing MDR-GNB.

In ASSEMBLE, 15 patients from nine countries (mean age 58.4 years, 60 percent male) were randomized 2:1 to receive either aztreonam-avibactam fixed-dose combination IV (+ metronidazole IV in complicated intra-abdominal infection [cIAI]) or BAT. In the microbiological intent-to-treat population, bloodstream infection (BSI) was the index infection in 33.3 percent of patients, followed by complicated urinary tract infection (cUTI; 26.7 percent) and ventilator-associated pneumonia (VAP; 20 percent). Two-thirds of the patients had previous treatment failure upon study entry.

The majority (60 percent) had a monomicrobial infection, with Enterobacterales overall being the most identified causative pathogen in 86.7 percent of patients. New Delhi MBL 1 (NDM-1)–positive Klebsiella pneumoniae (40 percent) was the most commonly cultured MBL-positive pathogen, followed by NDM-5–positive Escherichia coli (20 percent) and L1-positive Stenotrophomonas maltophilia (20 percent, none in the BAT arm).

Poor outcomes despite BAT

The BAT regimens employed in ASSEMBLE consisted of either meropenem + amikacin + polymyxin or amikacin + colistin. In both treatment arms, BSI, cUTI, and cIAI were treated for a minimum of 5 days, while nosocomial pneumonia was treated for a minimum of 7 days. All exposure to study treatment were <15 days.

The primary efficacy endpoint of adjudicated clinical cure at the test-of-cure visit was achieved in 41.7 percent (95 percent confidence interval, 18.0–68.8) of patients in the aztreonam-avibactam arm and 0 percent in the BAT arm, respectively. As specified in the protocol, no formal statistical comparisons between treatment arms were performed.

Of note, 25 percent of patients with previous treatment failures treated with aztreonam-avibactam had clinical cure. Clinical cure rates among those with the most commonly enrolled index infections were 75 percent for BSI, 66.7 percent for cUTI, and 0 percent for VAP. The clinical cure rate in nosocomial pneumonia was masked by 66.7 percent of indeterminate cure outcomes.

All-cause 28-day mortality rates were 8.3 percent in the aztreonam-avibactam arm and 33.3 percent in the BAT arm, which were also descriptive in nature.

The only serious adverse event deemed related to treatment occurred in the BAT arm, which was acute kidney injury, a common toxicity associated with lipopeptide antibiotics.

Data from ASSEMBLE “suggest a potential role for aztreonam-avibactam for treating serious infections caused by MBL-producing Gram-negative bacteria,” concluded the investigators.